The spread of artemisinin (ART)-resistant Plasmodium falciparum threatens the control of malaria and mutations in the propeller domains of P. falciparum Kelch13 (k13) are strongly associated with the resistance. Ferredoxin (Fd) in the ferredoxin/NADP+ reductase (Fd/FNR) redox system is essential for isoprenoid precursor synthesis in the plasmodial apicoplast; nonetheless, mutations of Fd gene (fd) may modulate ART resistance and Fd would be an important target for antimalarial drugs. We investigated the inhibitory effects of dihydroartemisinin (DHA), methoxyamino chalcone (C3), and iron chelators including deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol hybrid (DFP-RVT) against the growth of wild-type (WT) P. falciparum parasites and those with k13 and fd mutations. C3 showed antimalarial potency similar to the iron chelators. Surprisingly, combined treatments of DHA with the C3 or iron chelators showed moderately antagonistic effects against P. falciparum growth. No differences were observed among the mutant parasites with respect to their sensitivity to C3 and the chelators, or the interactions of these compounds with DHA. The data suggest that inhibitors of the Fd/FNR redox system should be avoided as ART partner drugs in ART combination therapy for treating malaria.

中文翻译：

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甲氧基氨基查耳酮衍生物和 3-羟基吡啶酮与双氢青蒿素联合对抗恶性疟原虫的拮抗抗疟特性

青蒿素 (ART) 耐药性恶性疟原虫的传播威胁着疟疾的控制，恶性疟原虫 Kelch13 (k13) 螺旋桨结构域的突变与耐药性密切相关。铁氧还蛋白/NADP+ 还原酶 (Fd/FNR) 氧化还原系统中的铁氧还蛋白 (Fd) 对于疟原虫顶端体中类异戊二烯前体的合成至关重要；尽管如此，Fd 基因 (fd) 的突​​变可能会调节 ART 耐药性，Fd 将成为抗疟药的重要靶点。我们研究了双氢青蒿素 (DHA)、甲氧基氨基查耳酮 (C3) 和铁螯合剂的抑制作用，包括去铁酮 (DFP)、1-(N-乙酰基-6-氨基己基)-3-羟基-2-甲基吡啶-4-酮 ( CM1) 和 deferiprone-resveratrol hybrid (DFP-RVT) 对抗野生型 (WT) 恶性疟原​​虫寄生虫和具有 k13 和 fd 突变的寄生虫的生长。C3 显示出与铁螯合剂相似的抗疟药效。令人惊讶的是，DHA 与 C3 或铁螯合剂的联合处理显示出对恶性疟原虫生长的适度拮抗作用。在突变寄生虫对 C3 和螯合剂的敏感性或这些化合物与 DHA 的相互作用方面没有观察到差异。数据表明，在治疗疟疾的 ART 联合疗法中，应避免将 Fd/FNR 氧化还原系统抑制剂作为 ART 伴侣药物。